Transgenic mouse models of Alzheimer disease (AD), such as the 3xTg-AD mice, are instrumental for elucidating genetic, pharmacologic, environmental, and behavioral factors that affect the cognitive phenotype. Here we present the novel findings that longitudinal water-maze spatial training produces a significant, albeit transient, improvement in subsequent learning performance and reduces A[unreadable] and tau neuropathology. The 3xTg-AD mice were trained and tested at 3 month intervals from 2 to 18 months. Separate groups of naive mice were also tested at each age. The improvement in performance seen at 6 to 12 months is dependent on spatial training, as animals that were similarly handled and exposed to swimming without a learning contingency failed to show improved performance. Training prior to the development of overt neuropathology is required for full expression of the training effect as we have found it delays A[unreadable] redistribution to extracellular plaques and reduces A[unreadable] oligomers associated with cognitive decline. In addition learning leads to decreased GSK3p activity which likely underlies the reduced tau pathology. The prior-training effects on both maze performance and neuropathology are attenuated at 15 and 18 months. These findings indicate that in young and middle-aged 3xTg-AD mice, repeated spatial training can significantly retard the development of neuropathology and cognitive decline. Aim 1: analyze the cognitive phenotype and determine how lifelong learning in 3xTg-AD mice affects the development of the neuropathology and learning and memory. Aim 2: determine the effects of ApoE4 on tau pathology and learning and memory. Aim 3: determine the impact of exacerbating tau phosphorylation in the presence or absence of A[unreadable] on learning and memory. These studies will lead to a better understanding of the genesis of learning and memory deficits in the 3xTg-AD mice and the relationship of plaques and tangles to cognitive impairments. This proposal represents an in-depth evaluation of learning and memory deficits in a model with both neuropathological hallmarks. More importantly, the outcome will have significant therapeutic implications, allowing us to elucidate the extent to which cognitive decline can be rescued in the context of a brain with both plaques and tangles, and allow us to begin to dissect the molecular mechanisms by which learning and memory are affected.